Sodium‐glucose co‐transporter‐2 inhibitor use and <i>JAK2</i> unmutated erythrocytosis in 100 consecutive cases
Authors: Naseema Gangat, Mostafa Abdallah, Natasha Szuber, Antoine Saliba, Hassan Alkhateeb, Aref Al‐Kali, Kebede H. Begna, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2023)

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors (canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin) referred to as "gliflozins" are FDA-approved for diabetes mellitus, heart failure, and chronic renal disease.1 It has been well-documented that SGLT-2 inhibitors significantly increase hemoglobin (Hgb) and hematocrit (Hct) levels which serve as a surrogate marker for cardiorenal protection.2, 3 Postulated shared mechanisms for erythrocytosis and cardioprotection include drug-induced hypoxia and nutrient-deprived state, in which activation of sirtuin 1 and hypoxia inducible factor (HIF2A), promotes erythropoietin (Epo) production.4, 5 Additional mechanisms for erythrocytosis include suppression of hepcidin, and hemoconcentration.6 In contemporary practice, SGLT-2 inhibitors are prescribed ubiquitously due to beneficial effects on diabetes mellitus, cardiovascular mortality, stroke and end-stage renal disease. Consequently, there has been an unprecedented rise in erythrocytosis referrals to hematology for patients on SGLT-2 inhibitor therapy, which are frequently triggered by Hgb/Hct levels that exceed thresholds for polycythemia (PV) (16.5 g/dL/49% and 16 g/dL/48% in Caucasian males and females, respectively).7 In general, treatment patterns in JAK2 unmutated erythrocytosis are markedly heterogenous due to inconsistencies in risk of thrombosis.8 Moreover, the outcomes of patients with SGLT-2 inhibitor-associated JAK2 unmutated erythrocytosis are not clearly defined. Accordingly, we sought to clarify these issues by looking into the presenting features, treatment strategies, and follow-up thrombotic events in patients with SGLT-2 inhibitor induced erythrocytosis that underwent hematological evaluation at our institution between October 2015 and November 2022. The current study comprised 100 consecutive patients with diabetes mellitus who received SGLT-2 inhibitor therapy and erythrocytosis defined by Hgb/Hct levels above 16.5 g/dL/49% in males and 16 g/dL/48% in females,7 and included 30 patients from a previously published cohort with additional follow-up.3 Study patients were retrospectively recruited after institutional review board approval. PV was excluded by JAK2 mutation (V617F) analysis in all cases; JAK2 (exon 12) and CALR/MPL mutation testing was performed in 63 and 33 patients, respectively. Additional investigations included abdominal imaging and overnight oximetry. Baseline Hgb/Hct prior to initiation of SGLT-2 inhibitor and peak Hgb/Hct values during therapy were recorded. Vascular events included major arterial thrombosis, myocardial infarction, angina, cerebrovascular accident, major venous thrombosis, deep vein thrombosis, and pulmonary embolism. Therapeutic interventions were dependent on physician discretion and included phlebotomy, blood donation, antiplatelet agents, and systemic anticoagulation, and a careful response assessment was performed to determine the impact of each therapy on thrombosis. A total of 100 patients with SGLT-2 inhibitor-associated JAK2 unmutated erythrocytosis (median age 62 years, range 29–87; 78% males) were studied. At the time of erythrocytosis evaluation, the majority of patients were on empagliflozin (n = 62), followed by dapagliflozin (n = 21) and canagliflozin (n = 17). A history of thrombosis was documented in 12 patients which included six arterial and venous events each. Additional causes for erythrocytosis were identified in 61 patients (Supplemental Table 1). Baseline median values (range) for Hgb/Hct were 15.5 g/dL (12–17.9 g/dL)/45.7% (36.7%–49%). Peak Hgb/Hct values of 18 g/dL (15.1–21 g/dL)/53.3% (48%–61.1%) with median increase from baseline Hgb/Hct of 2.5 g/dL (0.4–7.3 g/dL)/7.5% (1.8%–21.1%) were recorded at a median of 9 months (range; 1–57 months) following initiation of therapy. Dose dependent correlation with peak Hgb/Hct was noted with canagliflozin (300 vs. 100 mg) (p = .01 and .02) but not empagliflozin or dapagliflozin. Serum Epo measurement was inappropriately normal or increased in all informative cases (n = 91); median 13 mIU/mL (range; 4.2–50.6 mIU/mL). We did not find a significant correlation between serum Epo and baseline/peak Hgb/Hct or increase in Hgb/Hct (p > .1). Similarly, neither age nor gender impacted increase in Hgb/Hct levels (p > .1). Therapeutic interventions consisted of phlebotomy or blood donation in 29 patients. In addition, 68 patients received anti-platelet therapy (aspirin [n = 65] or clopidogrel [n = 3]), and 16 patients were on systemic anticoagulation. SGLT-2 inhibitor therapy was discontinued in 26 patients because of erythrocytosis (n = 4; 15%), poorly controlled diabetes mellitus (n = 4; 15%), yeast infection (n = 5, 19%), and urinary tract infection (n = 3; 12%). Serial Hgb/Hct values were available in 16 patients, and resolution of erythrocytosis was documented in all cases at a median of 2 months following discontinuation of therapy. Supplemental Table 1 summarizes presenting features and clinical outcomes including treatments utilized for all patients with SGLT-2 inhibitor-associated erythrocytosis. At a median follow-up of 24 months (range; 2–75 months) on SGLT-2 inhibitor, 10 thrombotic events were documented which included arterial (n = 7) and venous (n = 3) events. Figure 1 illustrates the timeline of thrombotic events including details on Hgb/Hct levels and active treatment at the time of event. Median age at time of thrombosis was 59 years, median Hgb/Hct 16.8 g/dL/49.7%, and median treatment duration 18 months (range; 5–33 months). Active therapies at the time of event included phlebotomy (n = 6), aspirin (n = 5), and systemic anticoagulation (n = 3). The thrombosis rates were significantly higher in males compared than in females (13% vs. 0%, p = .02). Neither baseline Hgb/Hct (p = .10 and 0.65), peak Hgb/Hct (p = .10 and .11), Hgb/Hct at the time of event (p = 1.0 and 1.0), age (p = .71), nor serum Epo (p = .31), appeared to correlate with thrombosis. The incidence of thrombosis was not significantly different among patients with an additional cause for erythrocytosis; (7/61 [12%] vs. 3/39 [8%], respectively; p = .53) or with history of smoking (1/15 [7%] vs. 9/85 [11%]; p = .62). Anti-platelet therapy and systemic anticoagulation also yielded similar rates of thrombosis; 7% versus 16% with or without anti-platelet therapy (p = .21) and 19% versus 8% with or without anticoagulation (p = .24). On the other hand, a significantly higher incidence of thrombosis was noted in patients who underwent phlebotomy; 21% (6/29) versus 6% (4/71) with or without phlebotomy (p = .03). In a separate analysis of arterial events (n = 7), thrombosis was more likely in males compared to females (9% vs. 0%, p = .15). Neither Hgb/Hct at the time of event (p = .12 and .15), baseline Hgb/Hct (p = .10 and .78), age (p = .71), nor serum Epo (p = .94), correlated with thrombosis. However, peak Hgb/Hct (p = .05 and .04) was found to be associated with increased thrombosis. Arterial thrombosis was also more likely in patients receiving phlebotomy; 17% (5/29) versus 3% (2/71) with or without phlebotomy (p = .02), while thrombosis rates were similar in patients on anti-platelet therapy (4% vs. 12%, p = .15) or systemic anticoagulation (19% vs. 5%, p = .10). The current study is the largest series on the clinical outcomes and management of patients with SGLT-2 inhibitor-associated erythrocytosis and provides an accurate review of thrombotic events during therapy, including the impact of therapeutic interventions. Whether elevated Hgb/Hct increases thrombotic risk in patients with JAK2 unmutated erythrocytosis continues to be an unresolved issue.9 We observed that neither baseline/peak Hgb/Hct nor Hgb/Hct at the time of event showed significant correlation with thrombosis. Moreover, implementation of phlebotomy did not appear to mitigate thrombotic risk; instead, thrombosis rates were higher in patients who underwent phlebotomy. These findings are consistent with Chuvash polycythemia in which thrombotic risk was found to be independent of elevated Hct and higher with phlebotomy.10 The current study does not implicate Hgb/Hct level as a major contributor of thrombosis in SGLT-2 inhibitor-associated erythrocytosis and underscores the limited therapeutic value of phlebotomy. Accordingly, the practice of phlebotomy in patients with drug induced JAK2 unmutated erythrocytosis should be re-evaluated and considering the beneficial effects of SGLT-2 inhibitors, premature discontinuation of therapy for erythrocytosis is not advised. Naseema Gangat and Ayalew Tefferi designed the study, compiled data, performed analyses and co-wrote the paper. Natasha Szuber introduced the study concept. Mostafa Abdallah compiled data. Antoine Saliba, Hassan Alkhateeb, Aref Al-Kali, Kebede H. Begna, and Animesh Pardanani contributed patients. All authors reviewed the final draft of the paper. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Supplemental Table 1. Clinical and laboratory characteristics of 100 patients with sodium-glucose co-transporter-2 (SGLT-2) inhibitor-associated JAK2 unmutated erythrocytosis Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.